Chronic myelocytic leukemia (CML) is a highly specific disease that is defined by strict hematologic parameters that include a pathognomonic differential leukocyte count. Usually, CML is accompanied by the presence, in bone marrow cells, of the Ph chromosome, the first chromosomal anomaly to be regularly associated with a human neoplastic disease. Chronic myelocytic leukemia is a disease of worldwide distribution and predominantly appears during middle age. The disease is characterized by an initial chronic phase when it behaves as a differentiated neoplasm and responds very well to simple, nonintensive therapy. After a variable interval, CML metamorphosizes to a refractory phase that responds poorly or not at all to therapy, even when intensive. See Spiers, Semin. Oncol., 22(4):380-95 (1995). At the stage of metamorphosis a great variety of clinical and hematologic pictures occur, and CML may mimic a myeloproliferative disease, a myelodysplasia, a subacute leukemia, acute myelocytic leukemia (AML), or acute lymphocytic leukemia (ALL). The old concept of an abrupt, explosive transition from the chronic phase to a so-called blastic crisis is incorrect. See Spiers, Semin. Oncol., 22(4):380-95 (1995). In most cases, CML is observed to undergo two or more stepwise evolutions, e.g., from chronic phase to an accelerated myeloproliferative phase to a phase that resembles AML.
A variety of therapies have been used to treat CML. Traditional methods for treating leukemia, including chemotherapy and radiotherapy, have limited utility due to toxic side effects. The use of monoclonal antibodies to direct radionuclides, toxins or other therapeutic agents selectively to tumor sites has reduced the level of toxicity to normal tissues. However, due to the large quantities of conjugate which must be administered, such therapies continue to produce toxic side-effects. These aspects limit the effectiveness and duration of such treatments. Another therapy, allogeneic bone marrow transplants, has had the largest impact on survival among patients with CML. See Clarkson, J. Clin. Oncol., 3:135-139 (1985). Like the previous therapies, however, bone marrow transplants are poorly tolerated by patients.
Recent studies suggest that immunotherapy utilizing naked antibodies can be an effective tool for treating certain cancers. The use of naked, humanized, anti-CD33 antibodies has proved effective in treating acute myelocytic leukemia and in reducing the residual disease in patients. See Caron et al., Clin. Cancer Res., 4:1421-1428 (1998); Jurcic et al., Clin. Cancer Res., 6:372-380 (2000). Similarly, immunotherapy comprising naked, humanized, anti-HER2/neu antibodies has produced promising results in the treatment of breast cancer. See Baselga et al., Semin. Oncol., 26:78-83 (1999); Weiner, Semin. Oncol., 26:43-51 (1999). Unconjugated immunoglobulins directed against CD20 have been shown to induce partial and complete responses in up to 50% of patients with advanced, indolent non-Hodgkin's lymphoma. See Weiner, Semin. Oncol., 26:43-51 (1999).
The use of naked antibodies for treating malignancies has several advantages. First, immunotherapy comprising solely naked antibodies lacks the toxic side-effects associated with other therapies, such as radioimmunotherapy (RAIT) or immunotherapy utilizing conjugated toxins. Second, circulating naked antibodies remain therapeutically active longer than other therapies. For example, the effectiveness of RAIT is limited by the half-life of the conjugated isotope, typically a week or less. Similarly, the efficacy of conjugated immunotoxins can be short-lived due to in vivo modification of the toxin. Third, since naked antibodies are well-tolerated by patients, multiple rounds of therapy can be administered. Fourth, combination therapy utilizing naked antibodies is better tolerated by patients because lower quantities of the toxic component of the combination are required to achieve effective results. Finally, the use of naked antibodies dramatically reduces the costs of treating cancer by reducing the need for expensive radioactive or therapeutic conjugates which possess short shelf-lives and whose administration typically requires special facilities and personnel. Thus, such cost reductions enable more patients to benefit from the therapy.
There is a need, therefore, to develop immunotherapies which utilize naked antibodies to treat CML. Such therapies would cost-effectively treat patients without inducing toxic side-effects